Quinoxalines are known which have antiviral or antibacterial action. For example, Acheson, J. Chem. Soc. 4731 (1950) reported that p-2'-quinoxalinylaminobenzoyl-(-)glutamic acid had a small growth-inhibitory effect on L. casei. The author also prepared 2-(2-diethylaminoethyl)aminoquinoxaline, the corresponding 6,7-dichloro derivative and the corresponding diethylaminopropyl derivative but found that all of these compounds were inactive against P. gallinaceum in chicks. 6,7-Dichloro-2-hydroxyquinoxaline-3-carboxylic acid and its ethyl ester were prepared and used as intermediates in the production of these diethylaminoalkylaminoquinoxalines. Abdulla et al, J. Het. Chem., 13, 427 (1976) used the 6,7-dichloro ester as an intermediate in the systhesis of the corresponding azeto[1,2-a]quinoxaline-1,3-dione. Belgium patent No. 769,491 (Derwent abstract 4493T supplied) discloses 2,3-dimercaptomethyl quinoxalines in which the benzene ring can be substituted with alkyl, alkoxy, halogen, trifluoromethyl, nitro, or alkylenedioxy. The compounds are said to be antiviral agents. 3,6-Diamino-2-quinoxaline carboxamides, stated to be useful as diuretics, anticonvulsant, anti-inflammatory agents, and to have antiviral activity against Herpes simplex, are disclosed in U.S. Pat. No. 3,192,212. A group of antiviral quinazolines (isomeric with quinoxalines) are disclosed in Belgium patent No. 815,196. A series of antiviral 2-chloro- or 2-hydrazinoquinoxalines are disclosed in three papers by Westphal, et al. Pharmazie, 32, 570-571, 687-689, 563-565 (1977). The following types of compounds were prepared: Quinoxaline- 2-ones substituted in the 3 position with a heterocyclic ring including benzimidazole, benzothiazole, or benzoxazole (no utility was given for these compounds); 2-chloro or 2-hydrazinoquinoxalines stated to be active against coxsackie B, vaccina, sindbas, and pseudorabies viruses; and, finally, a group of s-triazolo[4,3-a]quinoxalines, prepared by cyclizing a 2-hydrazinoquinoxaline, were allegedly useful against some of the above viruses.
In addition to the above listed antiviral agents having the basic quinoxaline structure, there has been a considerable amount of work carried out on quinoxaline-1,4-dioxides as antiviral agents. Much of this work is summarized in Hurst, et al., Brit. J. Pharmacol., 8, 297, (1953). According to this summary, quinoxaline-1,4-dioxides were the most active compounds tested in experimental psittacosis and lymphogranuloma venereum infections. A large number of derivatives of the quinoxaline-1,4-dioxides are summarized on page 301 of the article and include compounds with the following substituents in the quinoxaline ring: ethyl, ethoxymethyl, acetoxymethyl, 2-methyl-3-ethyl, 2-methyl-3-carboethoxy, 2,3-dihydroxymethyl, 2,3-diiodomethyl, 2,3-bis(dimethylaminomethyl), etc. Substituents in the benzene ring include: halogens, alkyl, nitro, trifluoromethyl, cyano, carboethoxy, carbamyl, acetamido, etc. (see also Derwent Abstract 5641U abstracting U.K. Pat. No. 1,305,138). A similar group of quinoxaline-1,4-dioxides is disclosed in Belgian patent No. 683,206, abstracted as Derwent No. 25,122. Substituted 2-formylquinoxaline-1,4-dioxides are disclosed in U.S. Pat. No. 3,433,871. The compounds are said to be antibacterial and antiviral compounds. U.K. Pat. No. 1,308,370 discloses an improved method of making substituted quinoxaline-1,4-dioxides having a variety of substituents in the quinoxaline ring including carboxamides (page 13), esters (page 15), a third ring (page 17-21), acyl derivatives (page 21), 3-hydroxy-2-alkoxycarbonyl derivatives (page 23), hydroxy carboxamides (page 24), etc. These compounds are alleged to have in vitro activity against harmful micro-organisms. Antiviral activity is not mentioned. Another patent relating to methods of preparing quinoxaline-1,4-dioxides, is U.K. Pat. No. 1,215,815. Page 1 of this patent reviews the literature briefly. 2-Hydroxy-3-carboalkoxyquinoxaline-1,4-dioxides are named specifically. Finally, U.S. Pat. No. 3,957,387 describes a group of carboxamidoquinoxalinedioxides. The compounds are alleged to be antibacterial substances.
The above survey of antiviral quinoxalines or quinoxalines containing various substituent groups and useful as either antiviral or antibacterial agents is not exhaustive and merely exemplary of the volumninous literature on the subject. It should be noted, however, that there has not been any public disclosure of quinoxalines having antiviral activity, particularly against both Maryland B and Ann Arbor strains of influenza virus in vivo. Such activity has, however, been disclosed in the copending application of Riaz Abdulla, Ser. No. 60,445 filed July 25, 1979, abandoned.
The antiviral activity of 1-aminoadamantane (amantidine, 1-adamantylamine) was first disclosed by Davies et al. Science, 144, 862 (1964). 1-Adamantylamine was the first of the highly hindered amines shown to have antiviral activity. 1-Adamantylamine is said to be active against influenza virus A.sup.2 strain prophylactically. The compound also may have some use in the propylaxis of Asian flu strains antigenically related to strain A.sup.2. 3-Methyl-1-aminoadamantane, dl-cyclooctylamine, 2-norbornylamine and 1-adamantyl-1-aminoethane (rimantadine) have all been shown to be antiviral agents.
U.S. patents relating to the use of adamantylamines as antiviral agents include U.S. Pat. Nos. 3,310,469 (1-aminoadamantane) 3,328,251 and 3,532,748 (2-aminoadamantanes) 3,592,934 (aminomethyladamantanes including rimantidine and aminomethyltricyclo[4.3.1.1.sup.3,8 ] undecanes). See also Herba Hung., 7, 115 (1968) for a review of virucidal (and oncolytic) activity of adamantylamines. Again, the above listing is not exhaustive, but exemplary only.